Field of the Invention
The present invention relates to the field of pharmaceutical chemistry, and in particular, to edaravone-gossypol derivatives with antitumor activities of and a method of preparing the same.
Discussion of the Related Art
Edaravone is a potent free radical scavenger with low molecular weight, high lipophilicity, and easy to reach biological target. It was approved and marketed in Japan in 2001 for cerebral hemorrhage, cerebral edema, and cerebral infarction treatment. Its free radical scavenging function and antioxidant effect has been confirmed and also used in adjuvant therapy for cancer patients in chemotherapy. Recent studies have shown that edaravone's mechanism of action involves many aspects, and its clinical application is not limited to ischemic stroke, extending to the field outside the nervous system. First, edaravone can inhibit xanthine oxidation enzyme and hypoxanthine oxidase activities, and stimulate cells to produce prostacyclin, reduce the release of leukotrienes, exhibit anti-tumor effect, and create synergies with radiotherapy and chemotherapy. Second, edaravone can directly remove hydroxyl groups, effectively inhibit the generation of lipid free radicals, and block the development of tumor by successfully inhibiting irreversible damage effect caused by the free radicals mediated by protein nucleic acid. Third, edaravone can inhibit the expression of aquaporin-4, and thus reduce edema associated with tumor. Edaravone has broad application and clinical value.
Gossypol is a polyphenolic bis-naphthalene aldehyde compound, and a natural yellow pigment found in small cell glands between cotton cells. Its structure was determined in 1938. Gossypol is recognized as an effective male contraceptive agent, but at the same time it also has large toxicity. The two aldehydes in its molecule not only play a role in tautomerization but also increase its chemical activities. They may contribute to its toxicity. As a new natural product with potential, in the early 1960s, the antitumor activity of gossypol was confirmed. Studies have shown that the anti-tumor mechanism of gossypol relates to its ability to inhibit the activation of topoisomerase II and the stability of topoisomerase-DNA complex formation, affecting cell functions. Gossypol also activates the expression of TGF-β1 in prostate cancer cell line PC3, and inhibits cell DNA synthesis and terminates cells in G0/G1 phase. In view of its antitumor activities, in recent years, the study of anti-tumor mechanism of gossypol has become active.
The present invention utilizes the aldehyde group of gossypol and the active site in the edaravone structure to synthesize edaravone-gossypol derivatives to achieve better anti-tumor activities and lower toxicities.